Interleukin-1 receptor type 1 – Myeloid differentiation primary response protein 88 interface (IL-1R1–MyD88 interface)

The Interleukin-1 receptor type 1 (IL-1R1) – Myeloid differentiation primary response protein 88 (MyD88) interface is a critical protein-protein interaction (PPI) site within the innate immune signaling pathway (UniProt P14778, Q99836). Upon binding of the pro-inflammatory cytokine IL-1 to the extracellular domain of IL-1R1, the receptor recruits the adapter protein MyD88 via a homotypic interaction between their respective Toll/interleukin-1 receptor (TIR) domains (Lin et al., Nature, 2010). This recruitment is the foundational step for the formation of the "myddosome" complex, which subsequently triggers a phosphorylation cascade involving IL-1 receptor-associated kinases (IRAKs) and ultimately activates the NF-κB transcription factor (Ve et al., 2015). Dysregulation of this interface is heavily implicated in chronic inflammatory diseases, autoimmune disorders, and certain malignancies where IL-1 signaling is constitutively active (Ngo et al., 2011). Pharmacological targeting of this specific interface aims to block downstream signaling more selectively than global IL-1 blockade, potentially offering a more nuanced therapeutic approach (Olson et al., 2015). Small molecule inhibitors like ST2825 and various peptidomimetics are being investigated to disrupt this TIR-TIR interaction to treat conditions such as rheumatoid arthritis and systemic inflammation (Loiarro et al., 2005). By specifically inhibiting the recruitment of MyD88 to IL-1R1, these agents can prevent the production of downstream pro-inflammatory cytokines like IL-6 and TNF-alpha (Bartfai et al., 2003). This target represents a significant opportunity for developing oral small-molecule alternatives to injectable biologics that target the IL-1 pathway.

Other names

IL-1R1-MyD88 TIR-TIR interfaceIL-1R1/MyD88 complexMyddosome assembly interfaceIL-1R1-MyD88 protein-protein interaction

Inhibition of protein-protein interaction (PPI) between the TIR domains of IL-1R1 and MyD88, preventing the recruitment of IRAK kinases and subsequent pro-inflammatory signaling.